Significant improvements in early post transplant survival rates have been achieved with induction of newer pharmacologic immunosuppressive agents over the last decade. Nevertheless, the need for further refinement of available therapeutic protocols is emphasized by the morbidity and the annual attrition rate of 3-4% observed in clinically treated allograft recipients, primarily as a result of chronic rejection. The objective of this Program Project is to improve the outcome following heart and lung transplantation by defining the essential conditions for and clarifying the mechanisms involved in donor-specific tolerance induction. The rational linking the objectives of the 3 inter-related Projects and 2 Core units is that since long-term donor-specific nonreactivity can be induced in many experimental models, including non-human primates, it should be possible to identify and reproducibly provide the immunologic perturbations which lead to this state in man. As "proof of principle" one approach employing mixed chimerism has achieved tolerance in several patients who received simultaneous kidney and bone marrow transplants from living donor MHG-matched siblings. In Project 1, Dr. Madsen and co-investigators will test three exciting new tolerance induction regimens alone and in combination to achieve synergy. In Project 2, Dr. Benichou and colleagues will investigate how memory T cells affect the ability of different protocols to achieve a state of tolerance in heart and lung recipients. In Project 3, Dr. Allan will apply the concept of mixed chimerism to lung transplantation for the first time. In the Immunopathology Core B, Dr. Colvin will provide the infrastructure and technology to perform morphologic, immunopathologic and molecular analysis of tissue and peripheral blood mononuclear cells provided by Projects 1 and 2. Dr. Madsen along with Dr. Schoenfeld will lead the Administrative and Biostatistics Core which will coordinate all administrative, statistical and data management issues of the Program Project. Our studies should yield clinically relevant information that will result in the development of new tolerance strategies applicable to heart and lung allografts recipients and lead to the development of better assays to monitor and predict patients that achieve tolerance and those at risk for the development of chronic graft loss.